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Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase
Mutations in the gene encoding the protein kinase CDKL5 cause a debilitating neurodevelopmental disease termed CDKL5 disorder. The impact of these mutations on CDKL5 function is poorly understood because the substrates and cellular processes controlled by CDKL5 are unclear. Here, we describe a quant...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293279/ https://www.ncbi.nlm.nih.gov/pubmed/30266825 http://dx.doi.org/10.15252/embj.201899559 |
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author | Muñoz, Ivan M Morgan, Michael E Peltier, Julien Weiland, Florian Gregorczyk, Mateusz Brown, Fiona CM Macartney, Thomas Toth, Rachel Trost, Matthias Rouse, John |
author_facet | Muñoz, Ivan M Morgan, Michael E Peltier, Julien Weiland, Florian Gregorczyk, Mateusz Brown, Fiona CM Macartney, Thomas Toth, Rachel Trost, Matthias Rouse, John |
author_sort | Muñoz, Ivan M |
collection | PubMed |
description | Mutations in the gene encoding the protein kinase CDKL5 cause a debilitating neurodevelopmental disease termed CDKL5 disorder. The impact of these mutations on CDKL5 function is poorly understood because the substrates and cellular processes controlled by CDKL5 are unclear. Here, we describe a quantitative phosphoproteomic screening which identified MAP1S, CEP131 and DLG5—regulators of microtubule and centrosome function—as cellular substrates of CDKL5. Antibodies against MAP1S phospho‐Ser(900) and CEP131 phospho‐Ser(35) confirmed CDKL5‐dependent phosphorylation of these targets in human cells. The phospho‐acceptor serine residues in MAP1S, CEP131 and DLG5 lie in the motif RPXSA, although CDKL5 can tolerate residues other than Ala immediately C‐terminal to the phospho‐acceptor serine. We provide insight into the control of CDKL5 activity and show that pathogenic mutations in CDKL5 cause a major reduction in CDKL5 activity in vitro and in cells. These data reveal the first cellular substrates of CDKL5, which may represent important biomarkers in the diagnosis and treatment of CDKL5 disorder, and illuminate the functions of this poorly characterized kinase. |
format | Online Article Text |
id | pubmed-6293279 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-62932792018-12-18 Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase Muñoz, Ivan M Morgan, Michael E Peltier, Julien Weiland, Florian Gregorczyk, Mateusz Brown, Fiona CM Macartney, Thomas Toth, Rachel Trost, Matthias Rouse, John EMBO J Resource Mutations in the gene encoding the protein kinase CDKL5 cause a debilitating neurodevelopmental disease termed CDKL5 disorder. The impact of these mutations on CDKL5 function is poorly understood because the substrates and cellular processes controlled by CDKL5 are unclear. Here, we describe a quantitative phosphoproteomic screening which identified MAP1S, CEP131 and DLG5—regulators of microtubule and centrosome function—as cellular substrates of CDKL5. Antibodies against MAP1S phospho‐Ser(900) and CEP131 phospho‐Ser(35) confirmed CDKL5‐dependent phosphorylation of these targets in human cells. The phospho‐acceptor serine residues in MAP1S, CEP131 and DLG5 lie in the motif RPXSA, although CDKL5 can tolerate residues other than Ala immediately C‐terminal to the phospho‐acceptor serine. We provide insight into the control of CDKL5 activity and show that pathogenic mutations in CDKL5 cause a major reduction in CDKL5 activity in vitro and in cells. These data reveal the first cellular substrates of CDKL5, which may represent important biomarkers in the diagnosis and treatment of CDKL5 disorder, and illuminate the functions of this poorly characterized kinase. John Wiley and Sons Inc. 2018-09-28 2018-12-14 /pmc/articles/PMC6293279/ /pubmed/30266825 http://dx.doi.org/10.15252/embj.201899559 Text en © 2018 The Authors. Published under the terms of the CC BY 4.0 license This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Resource Muñoz, Ivan M Morgan, Michael E Peltier, Julien Weiland, Florian Gregorczyk, Mateusz Brown, Fiona CM Macartney, Thomas Toth, Rachel Trost, Matthias Rouse, John Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase |
title | Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase |
title_full | Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase |
title_fullStr | Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase |
title_full_unstemmed | Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase |
title_short | Phosphoproteomic screening identifies physiological substrates of the CDKL5 kinase |
title_sort | phosphoproteomic screening identifies physiological substrates of the cdkl5 kinase |
topic | Resource |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6293279/ https://www.ncbi.nlm.nih.gov/pubmed/30266825 http://dx.doi.org/10.15252/embj.201899559 |
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